Immunity to viral infections includes both antibody and T cell components. The roles of those components differ under different physiological and genetic circumstances. We have used an in vivo challenge system to reexamine protective immunity to influenza, using as vaccines ten recombinant vaccinia vectors expressing the ten different proteins of influenza. The vaccinia vectors were well tolerated by both normal and beta-2 microglobulin-deficient mice (derived by Drs. Koller and Smithies, obtained from CellGenesys, Inc.). Normal mice were protected against challenge with live influenza virus by Hl-VAC and NA- VAC, the classical targets of antibody-mediated protection, but not by vaccinia vectors expressing the eight other flu proteins nor by a mixture of all eight of the latter vectors. Mice genetically deficient in beta-2 microglobulin and therefore expressing no conventional MHC class I antigens were protected in the same cases. Thus, the absence of class I restricted cytotoxic T lymphocytes did not alter observed patterns of protection under these conditions. Genetic control of protective responses and occurrence of cytotoxic T cell immunity are under investigation in mice of several MHC haplotypes.